rehmannia glutinosa

Rehmannia glutinosa: A Comprehensive Reference

1. Identity and Botanical Characterization

Taxonomic Classification and Naming

Rehmannia glutinosa, a widely used traditional Chinese herb, belongs to the family Scrophulariaceae. Some more recent taxonomic treatments place it in the family Orobanchaceae. Rehmannia refers to the root of Rehmannia glutinosa, and the species epithet glutinosa comes from glutinous, referring to the sticky nature of the root. The full taxonomic designation most commonly cited in pharmacological literature is Rehmannia glutinosa Libosch. The crude drug derived from its root is referred to in pharmacopoeial and clinical literature as Rehmanniae Radix. In Chinese, the plant and its root preparations are collectively known as Di Huang (地黄), with variant names depending on the form of processing (see below). Other common names in English include Chinese foxglove.

Rehmannia glutinosa is distributed in the provinces of Henan, Shandong, Shan'xi, Shanxi, Hebei, Liaoning, Inner Mongolia, Jiangsu, Zhejiang, Hunan, Hubei, and Sichuan in China, mainly cultivated but also wild in places such as mountain slopes and trails, from near sea level to 1,100 m.

Plant-Part Used and Botanical Description

Rehmanniae Radix (RR) refers to the fresh or dried root tuber of the plant Rehmannia glutinosa Libosch of the family Scrophulariaceae. Rehmanniae Radix is either the fresh or dried root of Rehmannia glutinosa Libosch., harvested in autumn, cleaned of reeds and fibrous roots, and either used fresh or slow-roasted until it is about 80% dry. The root tubers are fleshy, thick, and brownish-orange on the outside with a dark, glutinous interior when processed.

It is officially included in the Pharmacopoeia of the People's Republic of China. Rehmannia is in the Pharmacopoeia of the People's Republic of China. However, it is not on the United Kingdom's General Sale List and is not covered by a Commission E monograph in Germany. The U.S. Food and Drug Administration (FDA) has not granted generally recognized as safe (GRAS) status to rehmannia; it is available in the United States as a dietary supplement under the Dietary Supplement Health and Education Act of 1994.

Forms and Preparations

A defining feature of Rehmannia as a medicinal material is that its properties are significantly altered by processing. According to the processing method, there are three types of Rehmannia glutinosa used as medicinal materials: fresh rehmannia root (Xian Dihuang), with the effect of clearing away heat and promoting salivation, removing heat from the blood to stop bleeding; Rehmannia dried rhizome (Sheng Dihuang), with the effect of removing pathogenic heat from blood, nourishing Yin, and promoting the production of body fluids; and prepared rehmannia root (Shu Dihuang) with the effect of nourishing Yin and supplementing the blood and benefiting the marrow.

The processing of Rehmanniae Radix, which includes methods such as steaming and the classical "nine steaming and nine drying" technique, transforms it into "RR Praeparata." This process alters its medicinal properties from cold to warm and its flavor from bitter to sweet, and the function changes from clearing heat to nourishing.

Rehmanniae Radix is mainly available in four forms: fresh Rehmanniae Radix, raw Rehmanniae Radix, prepared Rehmanniae Radix, and nine-steamed, nine-dried Rehmanniae Radix. In modern supplement markets, Rehmannia is available as dried root, standardized aqueous or ethanolic extracts, capsules, tablets, and in traditional decoction form. The dried root of Rehmannia glutinosa is also a crude drug used in traditional Japanese Kampo medicine.

2. Traditional and Historical Use

China: Over Two Millennia of Use

Rehmannia has been used in China for over 2,000 years, with its earliest references found in classical texts such as the Shennong Ben Cao Jing (Divine Farmer's Materia Medica), compiled during the Han dynasty. Rehmanniae Radix was classified as a superior herb in this foundational text. It was classified as a "superior herb"—one that can be taken over long periods to preserve vitality and extend life.

Rehmannia Radix has been used in clinical practice for more than 3,000 years in China to reduce fever, improve blood circulation, tonify the kidney, and treat osteoporosis and Yin deficiency syndrome. In traditional Chinese medicine (TCM), it is taken to nourish Yin and invigorate the kidney.

R. glutinosa has been considered a panacea in traditional Chinese medicine, primarily in combination with other herbs. Dried Rehmannia rhizome is reputed to "nourish the yin" and remove heat from the blood, and is used as a tonic for the liver. Documented historical uses include treatment of anemia, cancer, constipation, diabetes, fatigue, bacterial and fungal infections, hypertension, insomnia, tinnitus, inflammatory conditions, burns, impotence, and osteoporosis.

Considered one of the 50 fundamental herbs of TCM, Rehmannia (Di Huang) is used to treat blood loss, bone injuries, lower back pain, uterine bleeding, and to regulate menses.

Traditional Preparations and Processing

TCM literature from the Later Han Dynasty to the present day documents the use of the dried root, which may be steamed for 3, 6, 9, or 12 hours, or soaked in yellow rice wine (liquor) prior to use, each approach producing preparations with somewhat distinct pharmacological profiles. Prepared Rehmannia (Shu Di Huang) has its root steamed with wine and then dried, which changes its properties and enhances its tonifying effects; this preparation is commonly used in TCM to nourish blood and Yin.

Traditional Formulas Containing Rehmannia

Rehmannia is a central ingredient in many classical TCM formulas. Rehmannia has been used for a variety of allergic, inflammatory, and autoimmune conditions in traditional Chinese medicine, including asthma, urticaria, eczema, rheumatoid arthritis, and chronic renal disease. Rehmannia has often been combined with Astragalus for managing inflammatory and immune disorders and is included in many traditional formulas for allergy, autoimmune disease, liver support, and chronic inflammation, including the kyon-ok-ko formula. Qi-ju-di-huang-wan (Lycium berry, Chrysanthemum, and Rehmannia pill) is commonly prescribed to Sjögren's patients, and Zhi-Bai-Di-Huang-Wan (Anemarrhena, Phellodendron, and Rehmannia pill) is commonly prescribed to lupus erythematosus patients.

Japan and Korea

The dried root of Rehmannia glutinosa is a crude drug used in traditional Japanese Kampo medicine as well as TCM. Rehmannia glutinosa is a plant very commonly used in Chinese and Korean traditional medicine for various disorders, including diabetes mellitus, neuronal disorders, and inflammation. In Korean traditional medicine, the fresh rhizome is known as Saeng-jihwang (SJH) and has been prescribed specifically for diabetes-associated complications.

3. Key Constituents and Active Compounds

Overview of Phytochemistry

More than 70 compounds, including iridoids, saccharides, amino acids, inorganic ions, as well as other trace elements, have been found in the herb. The primary phytochemicals identified in R. glutinosa include iridoid glycosides, phenethyl alcohol glycosides, polysaccharides, and various minor constituents. These compounds contribute to the plant's therapeutic properties, such as anti-inflammatory, antioxidant, and hypoglycemic effects.

The main components of Rehmanniae Radix include iridoid glycosides, phenylethanoid glycosides, anthraquinones, sugars, amino acids, volatile oils, and inorganic substances. From raw Rehmanniae Radix, 75 compounds have been extracted, which are categorized into classes such as iridoid glycosides, phenylethanoid glycosides, flavonoids, ionones, phenolic acids, and carbohydrates.

Iridoid Glycosides

Iridoid glycosides are among the most significant bioactive components in R. glutinosa. Key iridoid glycosides include aucubin, catalpol, and geniposide. More than 33 iridoid monomers, which are the most important components in the herb, as well as monoterpenes and glycosides, have been separated and identified, including: dihydrocatalpol, acetylcatalpol, leonuride, aucubin, melittoside, rehmaglutin A, B, C, D, cerebroside glutinoside, rehmannioside A, B, C, D, rehmaionoside A, B, C, rehmapicroside, purpureaside C, echinacoside, cistanoside A, F, jionoside A1, B1, jioglutoside A, B, geniposide, ajugoside, 8-epiloganic acid, ajugol, 6-O-vanilloylajugol, and martynoside.

Catalpol is the most extensively studied individual compound. Catalpol is an iridoid glycoside with the highest content in Rehmannia glutinosa Libosch, and it is also a key index component for evaluating the quality of Rehmannia glutinosa Libosch; since 2005, it has been continuously included in various editions of the China Pharmacopoeia. Catalpol is characterized by its polar structure, high solubility in water, and a molecular formula of C₁₅H₂₂O₁₀ with a molecular weight of 362.45.

Processing significantly alters catalpol concentrations. The most substantial decline in catalpol during wine stewing is from 44.00 mg/g in fresh Rehmanniae Radix to 2.192 mg/g in wine-stewed Rehmanniae Radix. With successive steaming from one to nine times, the concentrations of catalpol, rehmannioside D, leonuride, and verbascoside diminish.

Polysaccharides

Polysaccharides—biopolymers composed of several monosaccharides connected by glycosidic bonds—are the main active functional components of R. glutinosa. They are typically extracted and purified from the roots and stems of RG and have a relative molecular weight of 4 × 10³ to 5 × 10⁴ Da. Accumulating evidence confirms that Rehmannia glutinosa polysaccharides (RGPs) are complex heteropolysaccharides with a wide array of pharmacological activities, including immunomodulation, anti-aging, hypoglycemic, and antitumor effects, many of which are mediated through gut microecology modulation. Characteristic studies show galactose, glucose, and fructose to be the major sugars in the polysaccharides.

Phenethyl Alcohol Glycosides (Phenylethanoid Glycosides)

These compounds include acteoside (also known as verbascoside), echinacoside, and related structures. Compounds isolated from the roots of Rehmannia glutinosa include acteoside, leucosceptoside A, martynoside, isomartynoside, purpureaside C, jionoside A1, and jionoside B1. Acteoside is the basis of the acteosides tested in clinical trials for chronic kidney disease (see Section 5 below).

Other Minor Constituents

Rehmanniae Radix also contains amino acids and small amounts of β-sitosterol, all of which undergo changes after processing. Additionally, nucleosides such as adenosine and uridine have been detected, and their levels are influenced by steaming procedures.

4. Mechanisms of Action

Anti-inflammatory and Antioxidant Mechanisms

The compounds of Rehmannia glutinosa have demonstrated significant anti-inflammatory properties. Catalpol has been shown to inhibit the production of nitric oxide (NO) and suppress the expression of inducible nitric oxide synthase (iNOS), which are key mediators of inflammation. The water extract of fresh Rehmannia (SJH) has been shown to have high free radical scavenging activity in vitro and to decrease the level of intracellular reactive oxygen species (ROS) in THP-1 cells treated with advanced glycation end products (AGEs). SJH suppressed the expression of pro-inflammatory genes, including TNF-α, MCP-1, IP-10, COX-2, and iNOS; the activation of NF-κB; and the expression of RAGE, a receptor for AGEs.

Neuroprotective Mechanisms

Catalpol is an iridoid glycoside compound that has been shown to have antioxidant, anti-inflammatory, and other neuroprotective effects, as well as certain protective effects against Alzheimer's disease (AD), Parkinson's disease (PD), and neurological conditions such as hypoxic/ischemic injury. Elevated serotonin and brain-derived neurotrophic factor (BDNF) levels by catalpol significantly protect against depression and neurodegeneration. The traditional Chinese medicine compound Liuwei Dihuang Decoction can improve learning and memory ability in mice with senile dementia, and catalpol, the main active ingredient, can inhibit the apoptosis of neural stem cells through the blood-brain barrier.

Metabolic and Hypoglycemic Mechanisms

Catalpol has demonstrated increased mitochondrial biogenesis and activation of the PI3K/Akt pathway for insulin sensitizing effects. In alloxan-induced diabetic rats, Rehmannia glutinosa oligosaccharide (ROS) at 100 mg/kg for 15 days showed a significant decrease in blood glucose level and hepatic glucose-6-phosphatase activity with an increase in hepatic glycogen content, and also raised plasma insulin levels while lowering plasma corticosterone levels.

Immune-Modulatory Mechanisms

Although immunosuppressive fractions have been identified in Rehmannia, overall the plant is demonstrated to be immune-modulating, as have iridoid glycosides in general, one of the main active molecular groups in Rehmannia. Aqueous extract from a steamed root of R. glutinosa was reported to suppress the production of TNF-α and IL-1 in mouse astrocytes.

Renoprotective Mechanisms

Studies in progressive renal failure rats induced by 5/6 nephrectomy found that Rehmannia glutinosa reduced the serum creatinine level, 24-hour urinary protein excretion, and glomerulosclerosis, and it also inhibited the expression of angiotensin II, AT(1) receptor, TGF-beta1, and type IV collagen in the renal cortex.

Cardiovascular Mechanisms

Catalpol's cardiovascular protective effect has been linked to PI3K/Akt, apelin/APJ, and Jak-Stat signaling pathways.

Anti-aging Mechanisms

The anti-aging effect of R. glutinosa is attributed to enhanced function of hematopoietic stem cells (HSCs). Mice fed with R. glutinosa displayed characteristics of a slowed aging process, including decreased senescence and increased rate of survival. The R. glutinosa group showed decreased reactive oxygen species levels and the percentage of β-galactosidase-positive cells through downregulation of the cellular senescence-associated proteins p53 and p16, and R. glutinosa exerts anti-aging effects by maintaining the quiescence and decreasing the senescence of HSCs.

5. Scientific Evidence by Area of Use

5.1 Kidney Disease and Renoprotection

Evidence level: Moderate — there are randomized controlled human trials, but most use Rehmannia as part of a multi-herb combination or as an isolated extract fraction (acteosides), not as whole-root preparations alone.

A randomized controlled trial assessed the efficacy and safety of Rehmannia glutinosa acteosides used in combination with the angiotensin receptor blocker irbesartan to treat primary chronic glomerulonephritis. A total of 479 patients were recruited and randomly assigned to the treatment group (Rehmannia glutinosa acteosides, two 200-mg capsules twice daily; and irbesartan, 150 mg once daily) or the control group (irbesartan, 150 mg once daily). After 8 weeks of treatment, the treatment group showed a mean reduction in 24-hour proteinuria of 36.42% compared to baseline, which was significantly higher than the mean reduction from baseline of 27.97% in the control group (P = 0.0278). The conclusion was that the combination of Rehmannia glutinosa acteosides and irbesartan can reduce proteinuria more effectively than irbesartan alone.

A second randomized, parallel, controlled trial investigated the effectiveness of general acteoside of Rehmanniae leaves compared with piperazine ferulate in the treatment of primary chronic glomerulonephritis. A total of 400 patients were recruited and randomly assigned to the treatment group (general acteoside of Rehmanniae leaves, two 200 mg tablets twice daily) or the control group (piperazine ferulate, four 50-mg tablets twice daily). The primary outcome was 24-hour urinary protein; secondary outcome measures included estimated glomerular filtration rate (eGFR), erythrocyturia, and electrolytes. Both Rehmanniae leaves (acteosides) and piperazine ferulate effectively reduced proteinuria and erythrocyturia in the treatment of primary chronic glomerulonephritis.

Renal fibrosis represents the final common pathological pathway of nearly all chronic kidney disease (CKD), and Rehmanniae Radix, a botanical drug in TCM, has a long history of use for its nephroprotective properties. Animal studies have demonstrated renoprotective effects, but comprehensive controlled human trials focused on renal fibrosis specifically are limited.

5.2 Diabetes Mellitus and Blood Glucose Regulation

Evidence level: Moderate for human/clinical studies of multi-herb formulas; predominantly preclinical (animal, in vitro) for single-herb Rehmannia preparations.

A retrospective clinical study investigated the efficacy of Liuwei Dihuang Pill (Bolus of Six Drugs Including Rehmannia) as an adjunct to metformin in the treatment of elderly patients with Type-2 diabetes mellitus. Eighty patients admitted to Baoding Hospital of Traditional Chinese Medicine were enrolled; patients in the control group received oral metformin, while those in the observation group received Liuwei Dihuang Pill as an adjunct to metformin. The study examined blood glucose-related indicators, insulin resistance parameters, and inflammatory factors.

In animal models, a study investigated the effects of Rehmannia glutinosa individually as well as in combination with metformin in streptozotocin-induced diabetic Wistar rats. Rats received metformin (500 mg/kg), R. glutinosa (200 mg/kg), the combination, or served as diabetic controls for 30 days. A reduction in plasma glucose levels caused by the herb was not as significant as metformin compared to the diabetic control (p < 0.05).

A separate study evaluated the hypoglycemic effects of Rehmannia glutinosa (RG) alone and in combination with Coptis chinensis on high-fat-diet-induced diabetes in mice. Diabetic KK-Ay mice were treated for eight weeks; administration of RG alone and its combination could decrease the fasting blood glucose level, ameliorate glucose tolerance, and recover levels of total cholesterol, triglycerides, HDL-cholesterol, and LDL-cholesterol in sera of diabetic mice.

The proposed mechanistic basis includes blood sugar significantly decreasing when treated with water extracts of Rehmannia glutinosa in paraquat-induced insulin-resistant mice. As noted, these findings are preclinical. No adequately powered randomized trials testing isolated Rehmannia root for blood glucose in humans have been identified in the peer-reviewed literature to date.

5.3 Osteoporosis and Bone Metabolism

Evidence level: Preclinical (animal and cell-based) evidence is substantial; clinical trial evidence is largely based on multi-herb formulas containing Rehmannia.

Rehmanniae Radix Praeparata is a traditional herbal medicine for improving liver and kidney function. Ample clinical and pharmacological experiments show that it can prevent post-menopausal osteoporosis and senile osteoporosis. In vivo and in vitro experiments using a UHPLC-Q/TOF-MS-based metabolomics approach explored the preventing effect on glucocorticoid-induced osteoporosis (GIOP). It was found that Rehmanniae Radix Praeparata significantly enhanced bone mineral density, improved the micro-architecture of trabecular bone, and intervened in biochemical markers of bone metabolism in dexamethasone-treated rats. These results indicated that the Rehmanniae Radix Praeparata preparation had a notable preventing effect on GIOP.

Rehmanniae Radix Praeparata (Shudihuang), the steamed roots of Rehmannia glutinosa, has been demonstrated to have anti-diabetic and anti-osteoporotic activities. A study aimed to explore the protective effect and underlying mechanism on diabetes-induced bone loss found that it regulated alkaline phosphatase activity and osteocalcin levels, enhanced bone mineral density, and improved bone microarchitecture in diabetic rats. The compounds catalpol (CAT), acteoside (ACT), and echinacoside (ECH) from this preparation increased the proliferation and differentiation of osteoblastic MC3T3-E1 cells injured by high glucose and promoted the production of IGF-1 and expression of related proteins in BMP and IGF-1/PI3K/mTOR signaling pathways.

Based on TCM theory, clinically selected prescriptions for the treatment of diabetic osteoporosis include Bushen Zhuanggu Decoction, Zishen Jiangtang Pill, and Tanggukang Decoction—all of which include Rehmanniae Radix Praeparata; there are 107 identified clinical trials that used Rehmanniae Radix combined with other herbs to treat osteoporosis. Properly designed and well-controlled prospective studies are still needed to further demonstrate bone protective actions and safe use of this herb and its ingredients.

5.4 Neuroprotection and Neurological Conditions

Evidence level: Primarily preclinical (in vitro and animal); human clinical trials are limited and largely conducted in the context of multi-herb TCM formulas.

Rehmannia glutinosa is commonly used in neurodegenerative diseases, and its iridoid glycoside extract catalpol (CAT) displays antioxidant, antiapoptotic, and neuroprotective pharmacological effects. Catalpol exhibits anti-diabetic, cardiovascular protective, neuroprotective, anticancer, hepatoprotective, anti-inflammatory, and anti-oxidant effects in experimental studies.

Manninotriose, the main oligosaccharide in prepared Rehmanniae Radix, could significantly increase the cell survival rate of corticosterone-injured neurons and ameliorate downregulation of the glucocorticoid receptor (GR), zinc finger protein 268 (Zif268), and synapsin 1 (SYN1) genes, demonstrating neuroprotection against corticosterone-induced neurotoxicity. In addition, manninotriose could facilitate differentiation of bone marrow mesenchymal stem cells (BMSCs) into neurons, which might lead to new treatments for neurological disorders.

Regarding depression, Rehmannia glutinosa DC. (Scrophulariaceae) and Lilium lancifolium Thunb. constitute a classic anti-depressant combination in TCM, exhibiting pharmacological effects that include anti-depressive, anti-anxiety, and anti-inflammatory properties. Current clinical studies have demonstrated that Baihe Dihuang Decoction, a traditional Chinese herbal compound containing Rehmannia, is effective in treating depression. These clinical studies are predominantly small, conducted in China, and require independent replication.

5.5 Immune System Modulation

Evidence level: Predominantly preclinical.

Extensive in vitro and in vivo studies have established polysaccharides as the principal bioactive constituents responsible for the therapeutic effects of Rehmannia glutinosa. These RGPs exhibit a broad and promising spectrum of pharmacological properties, including immunomodulation, anti-inflammatory, antitumor, anti-aging, and metabolic regulatory activities, many of which are mediated through gut microbiota modulation.

Rehmannia glutinosa polysaccharide (RGP) is the main component of Rehmannia glutinosa, which can enhance immunity and promote the differentiation of bone marrow mesenchymal stem cells. No adequately designed randomized human trials examining immune outcomes with isolated Rehmannia polysaccharide preparations in healthy or immunocompromised human populations have been identified.

5.6 Anti-aging Effects

Evidence level: Preclinical only.

An animal study found that the anti-aging effect of R. glutinosa is due to enhanced function of hematopoietic stem cells. Mice fed R. glutinosa displayed characteristics of a slowed aging process, including decreased senescence and increased rate of survival. Flow cytometry analysis showed decreased numbers of LSK cells, long-term HSCs, and short-term HSCs in the R. glutinosa group. Clonogenic assays showed increased self-renewal ability of long-term HSCs from the R. glutinosa group, as well as maintained LSK quiescence through upregulated p18 expression.

Crude polysaccharides isolated from the aqueous extract of Rehmannia glutinosa have been shown to have robust anti-aging and stress resistance effects in the model organism Caenorhabditis elegans. Whether these findings translate to human aging outcomes has not been established.

5.7 Hematopoiesis and Anemia

Evidence level: Traditional use supported by limited preclinical data; human clinical data is largely from multi-herb formulas.

Modern pharmacological studies have shown that R. glutinosa has effects such as lowering blood sugar, improving the central nervous system, anti-tumor properties, delaying aging, and exhibiting antibacterial activity. Studies show that Rehmannia glutinosa and its active principles possess wide pharmacological actions on the blood system, immune system, endocrine system, cardiovascular system, and the nervous system.

5.8 Cardiovascular Effects

Evidence level: Preclinical.

As a traditional Chinese herbal medicine, Rehmannia glutinosa possesses multiple effects including analgesia, sedation, anti-inflammation, antioxidation, anti-tumor, immunomodulation, cardiovascular and cerebrovascular regulation, and nerve damage repair, and it has been widely used in clinical practice. However, dedicated cardiovascular human intervention trials specifically testing Rehmannia in isolation are not documented in the available peer-reviewed literature.

6. Body Systems and Health Areas of Association

• Urinary/Renal System: Tonifying the kidney; supported by human RCTs for proteinuria reduction in glomerulonephritis.
• Endocrine/Metabolic System: Actions on the endocrine system; hypoglycemic effects in preclinical and limited human (multi-herb) contexts.
• Nervous System: Commonly used in neurodegenerative diseases with catalpol as the primary neuroprotective agent in preclinical studies.
• Immune System: Immunomodulation mediated through gut microecology; established in preclinical models.
• Skeletal System: Commonly used clinically to prevent and treat osteoporosis; multiple animal studies and clinical formula trials support this.
• Blood/Hematopoietic System: Traditional use for anemia and blood loss; some preclinical evidence from hematopoietic stem cell research.
• Cardiovascular System: Preclinical evidence only; catalpol acts on PI3K/Akt and other cardioprotective pathways.
• Gastrointestinal System: Many pharmacological activities are mediated through gut microbiota modulation.

7. Dosage Forms and Reported Dosages

There is no proven safe or effective dose for rehmannia. Herbal decoctions used in clinical trials have contained 12–30 grams of rehmannia. Another dosing regimen reported in clinical contexts was 45–50 grams of Rehmannia glutinosa daily in five-day courses with an intermission of five days each time for 2–5 months.

In specific documented clinical trials:

• Rehmannia glutinosa acteosides: two 200-mg capsules twice daily, administered for 8 weeks, in combination with irbesartan 150 mg once daily, for chronic glomerulonephritis.
• General acteoside of Rehmanniae leaves: two 200-mg tablets twice daily for chronic glomerulonephritis.
• In a Wistar rat experiment, R. glutinosa was tested at 200 mg/kg (alongside metformin at 500 mg/kg) for 30 days.
• In a mouse study on insulin resistance, the observation group was given 1.2 g/kg/day of water extract of Rehmannia glutinosa.

When taken by mouth, rehmannia is considered possibly safe when used for up to 8 weeks. There is no proven safe or effective dose for rehmannia in children.

Modern supplement preparations include standardized capsules and tablets (often standardized to catalpol content), as well as traditional aqueous decoctions. Rehmannia extracts can vary greatly in strength, and there is no safe and effective dose established because no sufficiently powered study has been conducted to determine one.

8. Safety Considerations and Drug Interactions

Adverse Effects

Minor and transient adverse reactions have been reported and include gastrointestinal (GI) reactions (e.g., diarrhea, abdominal pain), edema, heart palpitations, fatigue, and vertigo. In a study of more than 400 patients with primary chronic glomerulonephritis, adverse drug reactions reportedly occurred at a similarly low rate in the treatment group (0.4%) and control group (1.2%; P=0.3724).

Toxicological Data

Aqueous extracts of Radix rehmanniae were not mutagenic in Salmonella assay tests; however, intraperitoneal administration of the extract at doses 10 to 40 times the human dose was mutagenic in mice. The extract of Rehmannia was evaluated for acute toxicity in mice using the LD50 and MTD methods, with no fatalities observed. A subchronic toxicity study was conducted on 80 Sprague-Dawley rats allocated into four groups: low (1,670 mg/kg), medium (8,330 mg/kg), high (16,700 mg/kg) doses of Rehmannia extract, and a control group. In that subchronic study, phenomena observed gradually normalized by days 2–3 and no animals exhibited symptoms of poisoning or mortality within 14 days post-treatment. While medicinal and edible plants are generally considered safe, they are not devoid of potential adverse effects, including side effects and toxicity, which may be dose-dependent, particularly in long-term studies.

Contraindications

Some ingredients in a combination preparation have been suspected to cause liver toxicity, and the Pharmacopoeia of the Republic of Korea lists liver disease as a contraindication to Rehmannia use. Chronic liver disease and GI disorders, including diarrhea, are listed as conditions where use should be avoided.

Drug Interactions

Rehmannia's potential to decrease blood sugar raises a moderate interaction concern with antidiabetic medications. Taking rehmannia with other medications for diabetes might cause blood sugar to decrease too much. Affected drug classes include sulfonylureas (e.g., glimepiride, glyburide, glipizide, tolbutamide, chlorpropamide), insulin, and thiazolidinediones (pioglitazone, rosiglitazone).

Because rehmannia might affect blood glucose levels, it might interfere with blood sugar control during and after surgery.

Pregnancy and Pediatric Populations

Rehmannia has traditionally been used as an emmenagogue. An anti-implantation effect in female mice has been recorded. There is no proven safe or effective dose for rehmannia in children.

Overall Evidence Limitations

Despite its long history in traditional medicine, there are relatively few studies on the efficacy of Rehmannia in isolation. Most available studies are based on animal models, and mice and rats do not always respond to diseases or treatments in the same way people do, so it is unknown whether the benefits will hold true in humans. Of the available studies on humans, many are of poor quality.

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